DNA methyltransferases (DNMTs) are enzymes that modify DNA. They add a methyl group to specific bases within DNA, a process known as DNA methylation. This modification is a component of epigenetics, involving changes in gene activity that do not alter the underlying DNA sequence. DNMTs regulate how genes are expressed and function within a cell.
The Role of DNA Methylation
DNA methylation is a natural process where a methyl group is added to a cytosine base, typically at a CpG site. This modification influences gene activity without changing the genetic code. By adding these methyl groups, DNA methylation alters how proteins interact with DNA, effectively turning genes “off” or “on.”
This process is important for controlling gene expression, enabling cells to develop into specialized types, and maintaining genome stability. For instance, DNA methylation helps ensure that genes specific to one cell type are silenced in others, maintaining cellular identity. It also contributes to the silencing of repetitive DNA elements, preserving genome integrity.
Types and Functions of DNA Methyltransferases
In mammals, three primary DNA methyltransferases are recognized for their roles in establishing and maintaining methylation patterns: DNMT1, DNMT3A, and DNMT3B. DNMT1 is primarily known as the “maintenance” methyltransferase. During DNA replication, DNMT1 recognizes existing methylation on the parental strand and copies this pattern onto the newly formed daughter strand, ensuring that methylation patterns are faithfully passed on to new cells. It has a strong preference for hemimethylated DNA.
DNMT3A and DNMT3B are often referred to as “de novo” methyltransferases because they establish new DNA methylation patterns on previously unmethylated DNA. These enzymes are particularly active during early development and gamete formation, setting up the initial methylation marks across the genome. DNMT3L, a related protein, lacks enzymatic activity but enhances the function of DNMT3A and DNMT3B, contributing to the establishment of methylation patterns.
Although traditionally categorized as maintenance or de novo, these functions are not entirely exclusive. DNMT1 can contribute to de novo methylation, and DNMT3A/3B can also participate in maintaining existing methylation patterns. The collaborative action of these DNMTs ensures that DNA methylation is dynamically regulated, allowing for both the establishment of new patterns and the stable inheritance of existing ones.
DNA Methyltransferases in Health and Disease
The precise regulation of DNA methylation by DNMTs is important for normal biological processes. DNMTs play a role in embryonic development, ensuring proper cell differentiation and tissue formation. They also contribute to the regulation of gene expression during cellular differentiation and aging. For example, DNMTs are widely expressed in the brain, influencing brain development, memory, and aging.
However, irregularities in DNMT activity or mutations in their genes can lead to diseases. In cancer, aberrant DNA methylation patterns are common. This can involve the hypermethylation of regions that regulate tumor suppressor genes, silencing their protective functions, or the hypomethylation of oncogenes or repetitive DNA elements, which can promote genomic instability and uncontrolled cell growth. Mutations in DNMT3A, for instance, are frequently observed in blood cancers like acute myeloid leukemia (AML).
Dysregulation of DNMTs and abnormal DNA methylation patterns are also linked to neurological disorders. Altered DNMT expression or mutations are associated with conditions such as Rett syndrome, Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease. These changes can disrupt gene expression in brain cells, impacting neural development, synaptic plasticity, and cognitive function.
Targeting DNA Methyltransferases
Given their involvement in disease, particularly cancer, DNMTs have become targets for therapeutic intervention. DNMT inhibitors aim to reverse abnormal DNA methylation patterns. Azacitidine and decitabine are two such inhibitors approved for the treatment of certain cancers, including myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML).
These drugs work by incorporating into newly synthesized DNA, where they bind to and trap DNMTs. This trapping prevents the DNMTs from carrying out their methylation activity, leading to hypomethylation. The goal of this treatment is to reactivate tumor suppressor genes silenced by excessive methylation in cancer cells, thereby restoring their normal function and potentially slowing or stopping cancer progression. Research continues to explore the full potential of targeting DNMTs in various diseases.